Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase
Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase
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DOI：
10.1021/ml5001273
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发表时间：
2015-01-01
影响因子：
4.2
通讯作者：
Linders, Joannes T. M.
中科院分区：
文献类型：
--
作者：
Johnson, Christopher N.;Adeinet, Christophe;Linders, Joannes T. M.
一种新的II型激酶抑制剂化学型已被确定为母体胚胎亮氨酸拉链激酶（MELK）使用基于结构的配体设计。该策略涉及通过蛋白质配体X射线晶体学对诱导的DFG外口袋进行结构表征，并掺入能够绕过大的看门人残基的细长连接，从而能够设计进入铰链和诱导口袋区域的分子。初始命中的优化导致鉴定出适合用作MELK的化学探针的低纳摩尔、细胞渗透的II型抑制剂。
A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by proteinligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.